Lung Cancer, Thoracic Oncology
Why Is Small Cell Lung Cancer So Difficult To Treat?
Small cell lung cancer (SCLC) is rarer than non-small cell lung cancer (NSCLC) but tends to be more difficult to treat. SCLC can be more resistant and aggressive than other cancers, which can increase the risk of relapses.
Survival rates for many types of cancer have improved drastically over the last several decades. Despite this, SCLC survival rates have remained less favorable.
From 2000 to 2016, the 5-year relative survival rate in the United States only improved from 6.0% to 8.7%.
Most cases of SCLC have already spread to distant body parts when they're diagnosed. This is because SCLC is an aggressive cancer. Even though many people respond to initial treatment, the majority experience relapse.
Researchers are still investigating why SCLC tends to be more resistant to treatment than most other cancers.
This article examines why SCLC is difficult to treat and reviews the most common current treatment options.
What is SCLC?SCLC accounts for 10% to 15% of lung cancers. Most other cases of lung cancer are classified as non-small cell lung cancer (NSCLC). SCLC tends to be more aggressive and more difficult to treat. It gets its name from the appearance of cancer cells under a microscope.
SCLC is often classified as limited stage if it's limited to one side of your chest and one radiation field. Extensive-stage SCLC has spread widely throughout your lung, to your other lung, or other parts of your body.
Learn more about SCLC.
SCLC tends to be difficult to treat due to its high risk of relapse, aggressive course of spread, and limited treatment options.
Resistant to treatment
More than 60% to 70% of people with SCLC have an initial response to chemotherapy. But after this initial response, many people relapse. Relapse often occurs within the first year of treatment.
It's still not clear why SCLC is more resistant to treatments than many other types of cancer. However, many types of immunotherapy and targeted therapy drugs are currently being evaluated as potential new treatments for SCLC.
Immunotherapy drugs recruit your immune system to destroy cancer cells. Targeted therapy drugs help destroy cancer cells while minimally damaging healthy cells.
Aggressive and quick to spread
SCLC tends to be very aggressive and spreads to other tissues quickly. When someone is diagnosed, the cancer may have already spread to their:
SCLC that has spread to distant parts of your body is called metastatic SCLC.
Symptoms often don't appear until later stages
People with SCLC often don't develop noticeable symptoms until the cancer reaches distant tissues. Early symptoms such as chest pain or a cough might be attributed to other causes, such as the flu.
In the United States, from 2012 to 2021, more than 70% of SCLC cases were diagnosed after they had reached distant body parts.
Fewer new treatments in development
Compared to NSCLC, relatively few new drugs have been approved to treat SCLC.
Between 2021 and 2023, the FDA approved six new medications for treating NSCLC and only one drug for SCLC that helps with chemotherapy symptoms.
SCLC tends to be an aggressive cancer that often relapses after someone initially responds to treatment. While the survival rate remains low, researchers are constantly looking into new potential treatment options.
A number of clinical trials are currently investigating the potential benefit of targeted therapies and immunotherapy drugs for treating advanced SCLC. Breakthroughs in these drugs may lead to future improvements in treatment.
The Role Of EGFR Mutations In Non-Small-Cell Lung Cancer Treatments
EGFR, epidermal growth factor receptor, is a protein found on the surface of your cells that makes them grow.
If you have non-small-cell lung cancer (NSCLC), your cancer might carry certain changes, or mutations, in your EGFR gene. Those changes make the protein made from this gene act in ways it shouldn't.
When that happens, your EGFR gets stuck "on." That makes your cells grow faster. It's important to note that EGFR is one of many mutations that can drive your cancer's growth.
Who Has NSCLC With EGFR Mutations?About 1 in 10 of all people with NSCLC have an EGFR mutation, but it's more common in some groups.
For example, about 1 in 3 Asian people with NSCLC have EGFR mutations.
It's even more common in people who have lung cancer but never smoked. About half of those lung cancer cases have an EGFR mutation.
If your NSCLC has this change, it's known as EGFR-positive. Having this mutation may affect your treatment options, especially if your cancer is more advanced.
Your doctor will likely treat your cancer using drugs that target EGFR, although you may have surgery or chemotherapy, too.
How Will My Cancer's EGFR Status Affect My Lung Cancer Treatment?Your doctor will help you decide the best way to treat your NSCLC based on many factors, including your cancer's EGFR status. Your doctor will consider:
Your EGFR status is an important consideration as you and your doctor choose the best way to treat your cancer.
Your cancer's EGFR status will matter most when your NSCLC has spread to distant parts of your body. When your lung cancer remains localized or hasn't spread very far, a surgeon may be able to remove it with surgery.
If it is caught early and can be removed fully with surgery, the specific type of cancer and mutations it has won't change your treatment or outlook. But most lung cancers aren't caught at this early stage.
What Are the Treatments for EGFR-Positive Lung Cancer?If you have advanced or stage IV NSCLC with EGFR-positive status, your doctor will likely treat your cancer with a targeted therapy.
These medicines are called EGFR inhibitors, or EGFR-targeted tyrosine kinase inhibitors (TKIs). These drugs block the EGFR signal that makes your cancer cells grow.
If you have stage III lung cancer and you're eligible for surgery, your doctor may have you take an EGFR inhibitor after surgery.
EGFR inhibitors most often used for advanced stage IV NSCLC include:
Osimertinib is approved for both early and more advanced EGFR-positive lung cancers.
You might take erlotinib along with another medicine called ramucirumab, which helps slow your cancer growth by blocking new blood vessels from forming.
If your advanced EGFR-positive NSCLC is a type known as squamous NSCLC, your doctor may use an EGFR inhibitor called necitumumab along with chemotherapy.
Your doctor will help you decide which EGFR inhibitor to try first. It'll depend on:
NSCLC can have different EGFR mutations. Your EGFR test results will tell your doctor what specific type of EGFR mutation your lung cancer has.
About 10%-15% of NSCLCs have a mutation that makes them more likely to respond to treatment with one of the more commonly used EGFR inhibitors or TKIs.
For NSCLCs with less common EGFR mutations, the specific mutation could lead to changes in how you're treated. One of these less common EGFR mutations is called an exon 20 insertion. About 2% of NSCLCs and 10% of EGFR-positive NSCLCs are this type.
Earlier, doctors used chemotherapy for this type of EGFR-positive NSCLC. Your doctor may still use chemo to treat it at first. But now there are targeted treatments for this type of EGFR mutation.
In 2021, the FDA approved amivantamab-vmjw, an EGFR and MET bispecific antibody, for advanced NSCLC with EGFR exon 20 mutations. It's approved for use if your SCLC with an EGFR exon 20 insertion keeps growing after chemotherapy.
What About Immunotherapy?Immunotherapiesare treatments that work by helping your immune system fight cancer. They've led to big improvements for some people with NSCLC.
However, immunotherapy often doesn't work well for treating EGFR-positive NSCLC. Scientists don't really know why.
Studies are ongoing to understand this better and find even more ways to treat EGFR-positive NSCLC.
What Is the Treatment Outlook for EGFR-Positive Lung Cancer?EGFR inhibitors can help you live longer if you have an advanced NSCLC that has EGFR mutations.
Treatment can help slow your cancer for months or years, but it won't cure your cancer.
One reason is that cancers treated with targeted therapy tend to find ways to resist treatment over time. Your cancer may pick up new mutations that enable it to keep growing despite treatment with EGFR inhibitors.
If this happens to you, your doctor might test your cancer again to see if it has mutations that might respond to a different targeted therapy. They might test it to see if it responds to immunotherapy or some other treatment.
You also may want to consider enrolling in a clinical trial that tests new treatments or new treatment combinations for EGFR-positive NSCLC.
Year In Review: Non-Small Cell Lung Cancer
The top stories in non-small cell lung cancer (NSCLC) for 2024 included practice-changing results in EGFR-mutant disease, an unprecedented gain in progression-free survival (PFS) for ALK-positive tumors, apparent superiority of perioperative versus neoadjuvant PD-(L)1 inhibition, and using novel agents to improve the anticancer activity of immunotherapy.
'Practice-Changing' Results for Inoperable Disease
Median PFS in unresectable, stage III EGFR-mutant NSCLC that did not progress after chemoradiation increased from 5.6 months with placebo to an "outstanding" 39.1 months with osimertinib (Tagrisso).
The 84% reduction in the risk of disease progression or death in PFS occurred despite the fact that 81% of patients randomized to placebo crossed over to osimertinib after disease progression, reported Suresh Ramalingam, MD, of Emory University's Winship Cancer Institute in Atlanta, at the American Society of Clinical Oncology (ASCO) meeting. An interim analysis of overall survival showed 3-year median values of 84% with the EGFR inhibitor versus 74% with placebo.
"Osimertinib will become the new standard of care for patients with locally advanced, non-small cell lung cancer following definitive chemoradiation," said Ramalingam.
ASCO-designated expert David Spigel, MD, of Sarah Cannon Research Institute in Nashville, Tennessee, added, "This will be practice changing. It really is outstanding."
The findings came from the international phase III LAURA trial involving 216 patients with unresectable, EGFR-mutant NSCLC and no evidence of disease progression after definitive chemoradiation. They were randomized 2:1 to osimertinib or placebo and followed until disease progression or unacceptable toxicity. The primary endpoint was PFS.
The findings create a mandate for EGFR mutation testing in all patients with stage III disease to identify those who might benefit from osimertinib, said Ramalingam.
The study outcome led directly to expanded FDA approval of osimertinib.
New Standard for First-Line ALK-Positive Disease
The risk of disease progression or death in newly diagnosed ALK-positive NSCLC decreased by 81% at 5 years when patients received the third-generation ALK inhibitor lorlatinib (Lorbrena) instead of crizotinib (Xalkori), the phase III CROWN trial showed.
Median PFS had yet to be reached in the lorlatinib arm as compared with 9.1 months in the crizotinib group. Median PFS values after 5 years were 60% with lorlatinib and 8% for patients randomized to the comparator.
"These results represent the most significant progression-free survival benefit that has been reported in ALK-positive lung cancer to date," said Benjamin Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, at the ASCO meeting.
ASCO Chief Medical Officer Julie Gralow, MD, called the findings "just unheard of."
The trial involved 296 patients with previously untreated, advanced NSCLC and test-confirmed ALK mutations. They were randomized to lorlatinib or crizotinib, and the primary endpoint was PFS.
The study outcome should be considered with the recognition that crizotinib is not used as often in the U.S. As in other countries, Spigel pointed out during an ASCO press briefing. How lorlatinib stacks up against newer drugs, such as alectinib (Alecensa) and brigatinib (Alunbrig), remains to be seen.
Meaningful Improvement in EFS With Perioperative Immunotherapy
Patients with resectable NSCLC had a 39% reduction in the risk of disease recurrence or death when treated with nivolumab (Opdivo) before and after surgery as compared with neoadjuvant-only nivolumab and chemotherapy, an exploratory comparison of two randomized trials showed.
The cross-trial comparison of the CheckMate 77T and CheckMate 816 trials likely represents the best, and perhaps last, chance for direct comparison of neoadjuvant versus perioperative immunotherapy in NSCLC, said Patrick Forde, MD, of Johns Hopkins Medicine in Baltimore, during the World Conference on Lung Cancer (WCLC) in San Diego.
"In the near future, we will not have a randomized trial available to use to try to make clinical decisions," said Forde. "And this analysis, at present, represents the only comparison of perioperative versus neoadjuvant-only immunotherapy treatments with resectable lung cancer."
Together, the results of CheckMate 77T and CheckMate 816 support perioperative therapy as a treatment option for eligible patients with resectable NSCLC, said invited discussant Nan Wu, MD, of Peking University Cancer Hospital in Beijing. Nonetheless, "phase III randomized clinical trials are needed for further validation."
CheckMate 77T showed an 18-month event-free survival (EFS) of 70% with perioperative therapy with nivolumab versus 50.0% with neoadjuvant-only chemotherapy, representing a 42% reduction in the hazard ratio. CheckMate 816 compared neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone and showed a median EFS of 31.6 months with nivolumab versus 20.8 months without, representing a 37% reduction in the EFS hazard.
At the WCLC, Forde reported findings from a propensity-matched analysis of the two randomized trials. The indirect comparison yielded a hazard ratio of 0.61 in favor of perioperative therapy. The results favored perioperative therapy regardless of disease stage and among patients with and without pathologic complete response to neoadjuvant therapy.
"However, we know that PD-L1-positive tumors tend to benefit from either neoadjuvant or perioperative or adjuvant therapy, so it's quite possible we need longer follow-up in this group," Forde observed.
Novel Agents Build on Activity of Neoadjuvant Immunotherapy
Three novel agents, an antibody-drug conjugate (ADC) and two monoclonal antibodies, showed promise for improving response to neoadjuvant durvalumab (Imfinzi) in resectable NSCLC.
Pairing the ADC datopotamab deruxtecan (Dato-DXd) with durvalumab and chemotherapy led to pathologic complete response (pCR) in 34% of patients and major pathologic response (mPR) in 65.9%. The anti-NKG2A antibody monalizumab plus durvalumab and chemotherapy resulted in a pCR rate of 26.7% and mPR of 53.3%. The addition of the anti-CD73 antibody oleclumab achieved a pCR rate of 20% and mPR of 45%.
For comparison, investigators used results of the phase III AEGEAN trial, which showed pCR and mPR rates of 17.2% and 33.0%, respectively with perioperative durvalumab plus chemotherapy, reported Tina Cascone, MD, PhD, of the University of Texas MD Anderson Cancer Center at the WCLC.
"This is the first global phase II study showing encouraging efficacy and manageable safety profile of antibody-drug conjugate in the neoadjuvant setting for patients with resectable non-small cell lung cancer," she said.
The results compared favorably with CheckMate 77T (pCR 25%) and CheckMate 816 (pCR 24%), Wu said during his discussion of the results. The findings require confirmation in randomized, phase III trials, he added.
Cascone reported findings from the NeoCOAST-2 trial, which represented a rational progression of clinical evaluation following earlier studies of durvalumab plus oleclumab or monalizumab in unresectable NSCLC and as neoadjuvant therapy for resectable disease. The trial involved a total of 202 patients, all of whom received neoadjuvant chemotherapy and were randomized to perioperative oleclumab-durvalumab, perioperative monalizumab-durvalumab, or neoadjuvant Dato-DXd and durvalumab followed postoperatively by durvalumab.
Other Newsworthy Developments in NSCLC
ACS Guidelines Expand Lung Cancer Screening Eligibility -- Is That a Good Thing?
Frontline EGFR/VEGF Inhibition Slows Advanced EGFR-Positive Lung Cancer
Trial Questions Role of Dual Immunotherapy in First-Line NSCLC
FDA Panel Supports More Clarity in NSCLC Perioperative Immunotherapy Trials
Novel Bispecific in EGFR-Mutant Lung Cancer Boosts PFS After Targeted Agents
Changing the Surgical Paradigm in Oligometastatic NSCLC
Futile Immunotherapy for Cancer Grows More Common
Please enable JavaScript to view the comments
Comments
Post a Comment